The present invention is generally related to 1-sulfonyl pyrrolidine derivitives showing affinity toward metabotropic glutamate receptors.
In the central nervous system (CNS) the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor.
L-glutamic acid, the most commonly occurring neurotransmitter in the CNS, plays a critical role in a large number of physiological processes. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group, namely the ionotropic receptors, forms ligand-controlled ion channels. The metabotropic glutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein-coupled receptors.
At present, eight different members of these mGluR are known and of these some even have sub-types. On the basis of structural parameters, the different influences on the synthesis of secondary metabolites and the different affinity to low-molecular weight chemical compounds, these eight receptors can be sub-divided into three sub-groups:
mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.
Ligands of metabotropic glutamate receptors belonging to the first group can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer""s disease, cognitive disorders and memory deficits, as well as chronic and acute pain.
Other treatable indications in this connection are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are Huntington""s chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depressions.
The present invention is a compound of the formula 
wherein
R1 signifies hydrogen or aryl, which is unsubstituted or substituted by halogen;
R2 signifies aryl, which is unsubstituted or substituted by halogen or lower alkyl;
R3 signifies xe2x80x94ORxe2x80x2, cyano, halogen, N-hydroxy-amidino, xe2x80x94C(O)xe2x80x94OR, xe2x80x94C(O)NRxe2x80x2Rxe2x80x3, xe2x80x94N(Rxe2x80x2)xe2x80x94C(O)xe2x80x94R4, xe2x80x94N(Rxe2x80x2)xe2x80x94S(O)2xe2x80x94R, xe2x80x94N(Rxe2x80x2)xe2x80x94C(S)xe2x80x94NRxe2x80x2xe2x80x3R or a 5- or 6-membered heteroaryl ring containing 1 to 4 N or O heteroatoms, said ring being unsubstituted or substituted by lower alkyl or cycloalkyl;
R4 signifies cycloalkyl, phenyl or lower alkyl, which is unsubstituted or substituted by halogen;
R signifies lower alkyl;
Rxe2x80x2 and Rxe2x80x2xe2x80x3 signify hydrogen, lower alkyl or cycloalkyl-lower alkyl;
Rxe2x80x3 signifies hydrogen, lower alkyl or lower alkyl substituted by a 5- or 6-membered heteroaryl ring containing from 1 to 4 N or O heteroatoms, said ring being unsubstituted or substituted by lower alkyl or cycloalkyl;
n is an integer from 0 to 5;
or its pharmaceutically acceptable salts.
It has been surprisingly found that the compounds of formula I possess affinity towards metabotropic glutamate receptors. Compounds of formula I are distinguished by valuable therapeutic properties.
Objects of the present invention are compounds of formula I and pharmaceutically acceptable salts thereof, racemic mixtures and their corresponding enantiomers, the above-mentioned compounds as pharmaceutically active substances, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of the compounds in accordance with the invention in the control or prevention of illnesses of the aforementioned kind, and, respectively, for the production of corresponding medicaments.
The present invention includes a compound of the formula 
wherein
R1 signifies hydrogen or aryl, which is unsubstituted or substituted by halogen;
R2 signifies aryl, which is unsubstituted or substituted by halogen or lower alkyl;
R3 signifies xe2x80x94ORxe2x80x2, cyano, halogen, N-hydroxy-amidino, xe2x80x94C(O)xe2x80x94OR, xe2x80x94C(O)NRxe2x80x2Rxe2x80x3, xe2x80x94N(Rxe2x80x2)xe2x80x94C(O)xe2x80x94R4, xe2x80x94N(Rxe2x80x2)xe2x80x94S(O)2xe2x80x94R, xe2x80x94N(Rxe2x80x2)xe2x80x94C(S)xe2x80x94NRxe2x80x2xe2x80x3R or a 5- or 6-membered heteroaryl ring containing from 1 to 4 N or O heteroatoms, said ring being unsubstituted or substituted by lower alkyl or cycloalkyl;
R4 signifies cycloalkyl, phenyl or lower alkyl, which is unsubstituted or substituted by halogen;
R signifies lower alkyl;
Rxe2x80x2 and Rxe2x80x2xe2x80x3 signify hydrogen, lower alkyl or cycloalkyl-lower alkyl, signifies hydrogen, lower alkyl or lower alkyl substituted by a 5- or 6-membered heteroaryl ring containing from 1 to 4 N or O heteroatoms, said ring being unsubstituted or substituted by lower alkyl or cycloalkyl, and
n is an integer from 0 to 5;
or pharmaceutically acceptable salts thereof.
Preferred compounds of formula I include a compound wherein R1 is hydrogen; R2 is aryl unsubstituted or substituted by halogen or lower alkyl; R3 and n are as defined above. An additional preferred compound includes a compound wherein R2 is p-tolyl and n is 3. Yet an additional preferred compound includes R3 as N(Rxe2x80x2)xe2x80x94C(O)xe2x80x94R4xe2x80x2 or 5- or 6-membered heteroaryl groups containing 1 to 4 heteroatoms selected independently from each other from N or O, which are unsubstituted or substituted by lower alkyl or cycloalkyl, and R4 is as defined above.
A further preferred compound has the structure 
wherein R3 and n are as above; and wherein R5 is hydrogen, halogen or lower alkyl. Additionally, compound I-A wherein R3 is xe2x80x94ORxe2x80x2, N-hydroxy-amidino, xe2x80x94C(O)NRxe2x80x2Rxe2x80x3 or xe2x80x94N(Rxe2x80x2)xe2x80x94C(O)xe2x80x94R4; R5 is halogen and n is 2 or 3 is preferred. Compound I-A is also preferred when R3 is ORxe2x80x2; R5 is ethyl; Rxe2x80x2 is as above and n is 1. Another preferred compound of formula I-A includes R3 being a 5- or 6-membered heteroaryl ring containing from 1 to 4 heteroatoms selected independently from each other from N or O, which is unsubsituted or substituted by lower alkyl or cycloalkyl with n as an integer between 0 and 5.
Another preferred compound of the present invention has the structure 
wherein R3 and n are as above.
A compound of formula I-B when R3 is an unsubstituted 5-membered heteroaryl group containing from 1 to 4 heteroatoms selected independently from each other from N or O is also preferred. Yet another preferred compound of formula I-B includes R3 as an unsubstituted 5-membered heteroaryl group containing from 1 to 4 nitrogen atoms and n is 0, 1 or 2. A compound of formula I-B is also preferred when the heteroaryl group includes at least one oxygen and n is 0, 1 or 2 or when n is 3, 4 or 5. An additional preferred compound of formula I-B includes R3 being a substituted 5-membered heteroaryl group containing 1 to 4 heteroatoms selected independently from each other from N or O; the 5-membered heteroaryl group containing from 1 to 4 nitrogen atoms with n as 0, 1 or 2; or the case where the substituted 5-membered heteroaryl group contains from 1 to 4 nitrogen atoms and n is 3, 4 or 5. An additional preferred compound of formula I-B includes R3 being a substituted 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from N or O and containing at least one N and at least one O wherein n is 0, 1 or 2; or when n is 3, 4, or 5.
Yet another preferred compound of formula I-B includes R3 being selected from xe2x80x94C(O)xe2x80x94OR, xe2x80x94C(O)NRxe2x80x2Rxe2x80x3, cyano, halogen, N-hydroxy-amidino, xe2x80x94N(Rxe2x80x2)xe2x80x94C(O)xe2x80x94R4xe2x80x94C(O)xe2x80x94OR, xe2x80x94N(Rxe2x80x2)xe2x80x94S(O2)xe2x80x94R and xe2x80x94N(Rxe2x80x2)xe2x80x94C(S)xe2x80x94NRxe2x80x2xe2x80x3R, wherein Rxe2x80x2, Rxe2x80x3, Rxe2x80x2xe2x80x3, R4 and R are as defined above.
Another preferred compound of formula I has the structure 
wherein R3 and n are as defined above. Another preferred compound of formula I-C includes R3 being xe2x80x94N(Rxe2x80x2)xe2x80x94C(O)R4; wherein R4 and Rxe2x80x2 are as defined above with n being 0, 1 or 2 or additionally when n is 3, 4 or 5. Yet another preferred compound of formula IV includes R3 being xe2x80x94N(Rxe2x80x2)xe2x80x94C(O)R4; wherein R4 and Rxe2x80x2 are as defined above; and n is 3, 4 or 5. A further preferred compound of formula I-C includes R3 being xe2x80x94C(O)NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 are as defined above.
An additional preferred compound of formula IV includes R3 being 5- or 6-membered heteroaryl groups containing from 1 to 4 heteroatoms selected independently from each other from N or O, which are unsubstituted or substituted by lower alkyl or cycloalkyl.
One further preferred compound of formula IV includes R3 being a substituted 5-membered heteroaryl group with n being 0, 1 or 2, or with n being 3, 4 or 5. Another preferred compound of formula I-C includes R3 being an unsubstituted 5-membered heteroaryl group with n being 0, 1 or 2 or the case when n is 3, 4 or 5. One more preferred compound of formula I-C includes R3 being xe2x80x94ORxe2x80x2 with Rxe2x80x2 is as above and n is 0, 1 or 2, or 3, 4 or 5.
Preferred compounds of formula I in the scope of the present invention are those, in which R3 signifies 5- or 6-membered heteroaryl groups containing from 1 to 4 heteroatoms selected independently from each other from N or O, which are optionally substituted by lower alkyl or cycloalkyl.
Especially preferred are compounds of formula I, wherein the heteroaryl group is selected from imidazole, pyrazole, [1,2,4]triazole, [1,2,4]oxadiazole or tetrazole, which is optionally substituted by lower alkyl or cycloalkyl.
The following are examples of such compounds:
(2RS,5SR)-5-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-]-ethyl}-3-methyl-[1,2,4]oxadiazole,
(2RS,5SR)-5-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-2-methyl-2H-tetrazole,
(2RS,5RS)-5-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-2-methyl-2H-tetrazole,
(2RS,5RS)-5-{4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1-methyl-1H-tetrazole,
(2R,5S)-5-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-2-methyl-2H-tetrazole,
(2R,5S)-5-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1-methyl-1H-tetrazole,
(2RS,5RS)-5-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1-methyl-1H-[1,2,4]triazole,
(2RS,5SR)-5-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1-methyl-1H-[1,2,4]triazole,
(2RS,5SR)-3-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1-methyl-1H-[1,2,4]triazole,
(2RS,5RS)-1-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-[1,2,4]triazole,
(2RS,5RS)-1-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-imidazole,
(2RS,5RS)-1-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-pyrazole,
(2RS,5RS)-1-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-tetrazole,
(2RS,5SR)-3-cyclopropyl-5-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-ylmethyl]-[1,2,4]oxadiazole,
(2RS,5SR)-1-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-[1,2,4]triazole,
(2R,5S)-1-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-[1,2,4]triazole,
(2S,5S)-1-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-imidazole,
(2S,5S)-1-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1H-pyrazole,
(2S,5S)-5-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-1-methyl-1H-[1,2,4]triazole,
(2RS,5RS)-1-{4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1H-[1,2,4]triazole,
(2RS,5RS)-2-{4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-2H-tetrazole,
(2S,5S)-1-{4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}1H-imidazole, or
(2S,5S)-1-{4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-1H-[1,2,4]triazole.
Further preferred compounds of formula I are those, wherein the heteroaryl group is selected from [1,3,4]oxadiazole or oxazole, which is optionally substituted by lower alkyl or cycloalkyl.
The following are examples of such compounds:
(2RS,5SR)-2-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-[1,3,4]oxadiazole,
(2RS,5SR)-2-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-methyl-[1,3,4]oxadiazole,
(2RS,5SR)-5-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-oxazole,
(2RS,5RS)-2-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-[1,3,4]oxadiazole, or
(2RS,5RS)-2-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-5-methyl-[1,3,4]oxadiazole.
Further preferred are compounds of formula I, in which
R3 signifies xe2x80x94N(Rxe2x80x2)xe2x80x94C(O)xe2x80x94R4 and
R4 signifies cycloalkyl or lower alkyl, which is optionally substituted by halogen.
The following are examples of such compounds:
(2RS,5SR)-cyclopropanecarboxylic acid [5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl-methyl]-amide,
(2SR,5SR)-cyclopropanecarboxylic acid {3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-amide,
(2S,5S)-cyclopropanecarboxylic acid {3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-amide,
(2SR,5SR)-N-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-acetamide,
(2RS,5RS)-N-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-propionamide,
(2RS,5RS)-N-{4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyl}-acetamide,
(2RS,5RS)-N-{5-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentyl}-acetamide,
(2S,5S)-N-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-acetamide,
(2RS,5RS)-2,2,2-trifluoro-N-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-acetamide, or
(2RS,5RS)-N-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-isobutyramide.
Also preferred are compounds of formula I, in which
R3 signifies xe2x80x94ORxe2x80x2 and
Rxe2x80x2 signifies hydrogen or methyl.
The following are examples of such compounds:
(2RS,5RS)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propan-1-ol,
(2S,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propan-1-ol,
(2RS,5SR)-2-(4-fluoro-phenyl)-5-(2-methoxy-ethyl)-1-(toluene-4-sulfonyl)-pyrrolidine,
(2RS,5RS)-2-(4-fluoro-phenyl)-5-(3-methoxy-propyl)-1-(toluene-4-sulfonyl)-pyrrolidine,
(2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butan-1-ol,
or
(2S,5S)-2-(4-fluoro-phenyl)-5-(4-methoxy-butyl)-1-(toluene-4-sulfonyl)-pyrrolidine.
Further preferred are compounds of formula I, in which
R3 signifies xe2x80x94C(O)NRxe2x80x2Rxe2x80x3 and
Rxe2x80x2 signifies hydrogen or lower alkyl and
Rxe2x80x3 signifies hydrogen, lower alkyl or lower alkyl substituted by a 5- or 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from N or O, which is optionally substituted by lower alkyl or cycloalkyl.
The following are examples of such compounds:
(2RS,5RS)-5-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-pentanoic acid amide, or
(2R,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionamide.
Compounds of formula I, in which
R3 signifies xe2x80x94N(Rxe2x80x2) S(O)2xe2x80x94R and
R signifies lower alkyl and
Rxe2x80x2 signifies hydrogen, lower alkyl or lower alkyl substituted by a 5- or 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from N or O, which is optionally substituted by lower alkyl or cycloalkyl,
are also preferred.
(2RS,5RS)-N-{3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propyl}-methanesulfonamide is an example of such a compound.
The invention embraces all stereoisomeric forms in addition to the racemates.
The term xe2x80x9clower alkylxe2x80x9d used in the present description denotes straight-chain or branched saturated hydrocarbon residues with 1 to 6 carbon atoms, preferably with 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, t-butyl and the like.
The term xe2x80x9ccycloalkylxe2x80x9d denotes a saturated carbocyclic group containing from 3 to 7 carbon atoms, preferred are cyclopropyl and cyclopentyl.
The term xe2x80x9ccycloalkyl-lower alkylxe2x80x9d denotes a lower alkyl residue as defined above which is substituted by a cycloalkyl group as defined above, preferred is cyclopropylmethyl.
The term xe2x80x9chalogenxe2x80x9d denotes fluorine, chlorine, bromine and iodine.
The term xe2x80x9carylxe2x80x9d means the monovalent aromatic carbocyclic radical consisting of one individual ring, or one or more fused rings in which at least one ring is aromatic in nature. Preferred aryl groups are phenyl or naphthyl.
The term xe2x80x9cheteroarylxe2x80x9d means the monovalent aromatic cyclic radical incorporating one or more heteroatoms. The term xe2x80x9c5- or 6-membered heteroaryl rings containing from 1 to 4 N or O heteroatomsxe2x80x9d embraces furyl, pyrrolyl, 1H-imidazolyl, 2H-imidazolyl, 4H-imidazolyl, 1H-pyrazolyl, 3H-pyrazolyl, 4H-pyrazolyl, 1,2-oxazolyl, 1,3-oxazolyl, 1H-[1,2,4]triazolyl, 4H-[1,2,4]triazolyl, 1H-[1,2,3]triazolyl, 2H-[1,2,3]triazolyl, 4H -[1,2,3]triazolyl, [1,2,4]oxadiazolyl, [1,3,4]oxadiazolyl, [1,2,3]oxadiazolyl, 1H-tetrazolyl, 2H-tetrazolyl, [1,2,3,4]oxatriazolyl, [1,2,3,5]oxatriazolyl, 1H-pentazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl and their dihydro derivatives. The heteroaryl ring is optionally substituted by lower alkyl or cycloalkyl.
Preferred are the following 5-membered heteroaryl rings: 1H-imidazolyl, 1H-pyrazolyl, 1H-[1,2,4]triazolyl, [1,2,4]oxadiazolyl, 4,5-dihydro-[1,2,4]oxadiazolyl, [1,3,4]oxadiazolyl, oxazolyl, 1H-tetrazolyl and 2H-tetrazolyl.
Preferred 6-membered heteroaryl groups are pyridyl or pyrimidyl.
The compounds of formula I and their pharmaceutically acceptable salts can be manufactured by reacting a compound of the formula 
with a compound of the formula 
to obtain a compound of formula 
and, if desired,
converting a functional group of R3 in a compound of formula I into another functional group,
and if desired,
converting a compound of formula I into a pharmaceutically acceptable salt.
Compounds of formula I may also be obtained directly by simply exchanging the functional group at position R3 by another functional group.
In accordance with the invention, an appropriately substituted compound of formula II, for example methyl (2RS,5SR)-5-(4-fluorophenyl)-1-pyrrolidine-2-carboxylate, is reacted with a suitable compound of formula III, for example toluene-4-sulfonyl chloride and triethylamine (see Scheme 1). R1, R3 and n have the significance given earlier. The reaction according to known methods is carried out at room temperature within 16 hours in an inert solvent, for example in dichloromethane. 
A compound of formula II is prepared by reacting a suitable compound of formula V with diethyl acetaminomalonate (IV) followed by hydrogenation on platinum oxide according to Scheme 2 or, for the case when R1 is H (see Example 84), DL-proline methyl ester can be used as starting material. 
A stereoselective synthesis of a compound of formula II can be achieved by reacting optically pure N-Boc-pyroglutamate with (4-fluoro-phenyl)magnesium bromide according to the methods described in Tetrahedron Letters 34, 6317-6320, 1999, J. Med. Chem. 39, 2594-2608, 1996 and Tetrahedron: Asymmetry 10, 2245-2303, 1999.
Scheme 3 shows how prolongation of the side chain starting with a compound of formula Ia, for example (2RS, 5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (Example 1), can be achieved. For instance, after reduction with lithium aluminium hydride to the corresponding alcohol, mesylation and nucleophilic substitution by cyanide compounds of formula Ic having a side chain with 2 C-atoms are obtained. Compounds of formula Ia1 containing 3 C-atoms in the side chain are prepared by oxidation of the alcohol to the aldehyde VII followed by Wittig reaction and hydrogenation. 
Tetrazolyl derivatives of formula If (e. g. Examples 27, 39, 40, 49, 50) can be prepared by a 1,3-dipolar addition of sodium azide to a nitrile of formula Ic1. The nitrile is preferably obtained by converting the ester group of a compound of formula Ia2 into the amide and dehydrating the amide with phosphorus oxychloride. Methyl-1,2,4-Triazolyl derivatives of formula Ig (e.g. examples 26, 69, 70) can be manufactured by addition of methylhydrazine to the nitrile. The cyano group of a compound of formula Icd can further be hydrogenated to the corresponding amine, which may be acylated with a suitable acylchloride to obtain a compound of formula Ie (e.g. examples 9, 15, 16). The acylation is preferably carried out with pyridine in dichloromethane. An overview of these reactions is given in Scheme 4 below. R4 has the significance given earlier. 
The formation of a 1,2,4-oxadiazolyl ring can be achieved by condensation of an acid of formula VIII with N-hydroxy-acetamidine as follows: a solution of the acid and 1,1xe2x80x2-carbonyl-diimidazole is stirred in DMF at room temperature for 2 h. N-hydroxy-acetamidine is then added and the reaction mixture is heated to 80xc2x0 C. for 16 h. After evaporation and solvation in acetic acid the reaction mixture is heated under reflux conditions for 2 h and after purification using known methods a compound of formula Ih (e.g. Example 25) is obtained (see Scheme 5).
1,2,4-Oxadiazolyl derivatives of formula Ij (e.g. Example 13) can be manufactured from the nitrile of formula Ic1 by reaction with hydroxylamine hydrochloride to obtain the carboxamidine Ii, which is condensed with acetic acid in DMF in the presence of 1,1xe2x80x2-carbonyl-diimidazole to form the 1,2,4-oxadiazolyl ring. 
The hydroxyl group of a compound of formula Ib1 can be methylated by known methods to obtain a compound of formula Im or substituted by a halogen atom. For example, reaction with thionylchloride yields the corresponding chloralkyl derivative (Ik). The halogen atom can further be substituted with a cyclic amine, for example 1,2,4-triazol (see Example 82), with the help of sodium hydride at 0xc2x0 C. The product, a compound of formula II, is purified by known methods. In Scheme 6, X signifies, independently from each other, a N-atom or a C-atom. 
The pharmaceutically acceptable salts can be manufactured readily according to methods known per se and taking into consideration the nature of the compound to be converted into a salt. Inorganic or organic acids such as, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like are suitable for the formation of pharmaceutically acceptable salts of basic compounds of formula I. Compounds which contain the alkali metals or alkaline earth metals, for example sodium, potassium, calcium, magnesium or the like, basic amines or basic amino acids are suitable for the formation of pharmaceutically acceptable salts of acidic compounds.
The compounds of formula I and their pharmaceutically acceptable salts possess, as already mentioned above, affinity towards metabotropic glutamate receptors (group 1 mGlu receptors) and can be used for the treatment or prevention of acute and/or chronic neurological disorders, such as psychosis, schizophrenia, Alzheimer""s disease, cognitive disorders and memory deficits, as well as acute and chronic pain. Other treatable indications are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are Alzheimer""s disease, Huntington""s chorea, ALS, dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficient functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, psychoses, opiate addiction, anxiety, vomiting, dyskinesia and depression.
The pharmacological activity of the compounds was tested using the following method: cDNA encoding rat mGlu 1a receptor was transiently transfected into EBNA cells using a procedure described by E.-J. Schlaeger and K. Christensen (Transient gene expression in mammalian cells grown in serum-free suspension culture; Cytotechnology, 30:71-83, 1999). [Ca2+]i measurements were performed on mGlu 1a transfected EBNA cells after incubation of the cells with Fluo-3 AM (0.5 xcexcM final concentration) for 1 hour at 37xc2x0 C. followed by 4 washes with assay buffer (DMEM supplemented with Hank""s salt and 20 mM HEPES. [Ca2+]i measurements were done using a fluorometric imaging plate reader (FLIPR, Molecular Devices Corporation, La Jolla, Calif., USA). When compounds were evaluated as antagonists they were tested against 10 xcexcM glutamate as agonist.
The inhibition (antagonists) or activation (agonists) curves were fitted with a four parameter logistic equation giving EC50, IC50, and Hill coefficient using the iterative non linear curve fitting software Origin (Microcal Software Inc., Northampton, Mass., USA).
The compounds of the present invention are group 1 mGlu receptor agonists. All of the compounds of the invention show activities, as measured in the assay described above, of 10 xcexcM or less, typically 1 xcexcM or less, and ideally of 0.3 xcexcM or less.
In the table below are shown some specific activity data:
The compounds of formula I or the pharmaceutically acceptable salts thereof can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formula I and pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula I, but as a rule are not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
In addition, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants and the like. They can also contain still other therapeutically valuable substances.
As mentioned earlier, medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of such medicaments which comprises bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.
The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/kg/day being preferred for all of the indications described. The daily dosage for an adult human being weighing 70 kg accordingly lies between 0.7-1400 mg per day, preferably between 7 and 700 mg per day.
Finally, as mentioned earlier, the use of compounds of formula I and of pharmaceutically acceptable salts thereof for the production of medicaments, especially for the control or prevention of acute and/or chronic neurological disorders of the aforementioned kind, is also an object of the invention.